Indole derivatives as histamine 3 receptor inhibitors for the treatment of cognitive and sleep disorders, obesity and other CNS disorders

ABSTRACT

This invention relates to compounds having pharmacological activity, to compositions containing these compounds, and to a method of treatment employing the compounds and compositions. More particularly, this invention concerns certain indole derivatives and their salts and solvates. These compounds have H 3  histamine receptor antagonist activity. This invention also relates to pharmaceutical compositions containing these compounds and to a method of treating disorders in which histamine H 3  receptor blockade is beneficial.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application of the U.S.nonprovisional application Ser. No. 12/284,574 filed Sep. 23, 2008 whichis a continuation of U.S. nonprovisional application Ser. No. 11/581,631filed Oct. 16, 2006 which claims priority of U.S. provisional patentapplication Ser. No. 60/726,793 filed Oct. 14, 2005, the disclosure ofwhich is incorporated herein by reference.

TECHNICAL FIELD

This invention relates to compounds having pharmacological activity, tocompositions containing these compounds, and to a method of treatmentemploying the compounds and compositions. More particularly, thisinvention concerns certain indole derivatives and their salts andsolvates. These compounds alter H₃ histamine receptor activity. Thisinvention also relates to pharmaceutical compositions containing thesecompounds and to a method of treating disorders in which histamine H₃receptor blockade is beneficial.

BACKGROUND OF THE INVENTION

Histamine is a chemical messenger involved in various complex biologicalactions. When released, histamine interacts with specific macromolecularreceptors on the cell surface or within a target cell to elicit changesin many different bodily functions. Various cell types including smoothmuscle, blood cells, cells of the immune system, endocrine and exocrinecells as well as neurons respond to histamine by modulating theformation of intracellular signals, including of phosphatidylinositol,or adenylate cyclase. Evidence that histamine plays a role as aneurotransmitter was established by the mid-to-late 1970's (Schwartz,1975) Life Sci. 17:503-518. Immunohistochemical studies identifiedhistaminergic cell bodies in the tuberomammillary nucleus of theposterior hypothalamus with widespread projections in the dicencephalonand telencephalon (Inagaki et al., 1998) J. Comp. Neural. 273:283-300.

Two histamine receptors (H₁ and H₂) were reported to mediate thebiochemical actions of histamine on neurons. More recently, studies havedemonstrated the existence of a third subtype of histamine receptor, thehistamine H₃ receptor (Schwartz et al., 1986) TIPS 8: 24-28. Variousstudies have now demonstrated that histamine H₃ receptors are found onthe histaminergic nerve terminals in the brains of several species,including man (Arrang et al., 1983) Nature 302: 832-837. The H₃ receptorfound on the histaminergic nerve terminal was defined as an autoreceptorand could intimately control the amount of histamine released from theneurons. Histamine, the natural compound, was capable of stimulatingthis autoreceptor but testing of known H₁ and H₂ receptor agonists andantagonists suggested that the H₃ receptor has a distinctpharmacological profile. Further, H₃ receptors have been identified oncholinergic, serotoninergic and monoamine nerve terminals in theperipheral nervous system (PNS) and central nervous system including thecerebral cortex and cerebral vessels. These observations suggest that H₃receptors are uniquely located to modulate histamine as well as otherneurotransmitter release, and compounds that bind H₃ receptors could beimportant mediators of neuronal activity.

As stated, CNS histaminergic cell bodies are found in the magnocellularnuclei of the hypothalamic mammillary region and these neurons projectdiffusely to large areas of the forebrain. The presence of histaminergiccell bodies in the tuberomammillary nucleus of the posteriorhypothalamus, a brain area involved in the maintenance of wakefulness,and their projections to the cerebral cortex suggest a role inmodulating the arousal state or sleep-wake cycle. The histaminergicprojection to many limbic structures such as the hippocampal formationand the amygdaloid complex suggest roles in functions such as autonomicregulation, control of emotions and motivated behaviors, and memoryprocesses.

The concept that histamine is important for the state of arousal, assuggested by the location of histaminergic pathways, is supported byother types of evidence. Lesions of the posterior hypothalamus are wellknown to produce sleep. Neurochemical and electrophysiological studieshave also indicated that the activity of histaminergic neurons ismaximal during periods of wakefulness and is suppressed by barbituratesand other hypnotics. Intraventricular histamine induces the appearancesof an arousal EEG pattern in rabbits and increased spontaneous locomotoractivity, grooming and exploratory behavior in both saline andpentobarbital-treated rats.

In contrast, a highly selective inhibitor of histidine decarboxylase,the sole enzyme responsible for histamine synthesis, has been shown toimpair waking in rats. These data support the hypothesis that histaminemay function in modulating behavioral arousal. The role of the H₃receptor in sleep-waking parameters has been demonstrated (Lin et al.,1990) Brain Res. 592: 325-330. Oral administration of RAMHA, a H₃agonist, caused a significant increase in deep slow wave sleep in thecat. Conversely, thioperamide, a H₃ antagonist/inverse agonist, enhancedwakefulness in a dose-dependent fashion. Thioperamide has also beenshown to increase wakefulness and decrease slow-wave and REM sleep inrats. These findings are consistent with in vivo studies demonstratingthat thioperamide caused an increase in synthesis and release ofhistamine. Together, these data demonstrate that selective H₃antagonists or inverse agonists may be useful in the treatment ofarousal states and sleep disorders.

Serotonin, histamine, and acetylcholine have all been demonstrated to bediminished in the Alzheimer's (AD) brain. The histamine H₃ receptor hasbeen demonstrated to regulate the release of each of theseneurotransmitters. An H₃ receptor antagonist or inverse agonist wouldtherefore be expected to increase the release of these neurotransmittersin the brain. Since histamine has been demonstrated to be important inarousal and vigilance, H₃ receptor antagonists or inverse agonists mightenhance arousal and vigilance via increasing levels of neurotransmitterrelease and thereby improve cognition. Thus, the use of compounds thatbind the use of H₃ receptor in AD, attention deficit disorders (ADD),age-related memory dysfunction and other cognitive disorders would besupported.

H₃ receptor antagonists or inverse agonists may be useful in treatingseveral other CNS disorders. It has been suggested that histamine may beinvolved in cerebral circulation, energy metabolism, and hypothalmichormone secretion. For example, H₃ receptor antagonists or inverseagonists have been demonstrated to affect food intake and body weightgain in rodents. Recent evidence has indicated the possible use of H₃antagonists or inverse agonists in the treatment of epilepsy. Work hasdemonstrated an inverse correlation between the duration of clonicconvulsions and brain histamine levels. Thioperamide was also shown tosignificantly and dose-dependently decrease the durations of everyconvulsive phase after electrically-induced convulsions and increase theelectroconvulsive threshold.

In spite of their low density, H₃ receptor binding sites can be detectedoutside the brain. Several studies have revealed the presence of H₃heteroreceptors in the gastrointestinal tract, as well as upon neuronsof the respitory tract. Accordingly, an H₃ receptor binding compound maybe useful in the treatment of diseases and conditions such as asthma,rhinitis, airway congestion, inflammation, hyper and hypo motility andacid secretion of the gastrointestinal tract. Peripheral or centralblockage of H₃ receptors may also contribute to changes in bloodpressure, heart rate and cardiovascular output and could be used in thetreatment of cardiovascular diseases, and in the treatment of diseasesor conditions such as obesity, migraine, inflammation, motion sickness,pain, ADHD, dementia, depression, Parkinson's disease, schizophrenia,epilepsy, narcolepsy, acute myocardial infarction and asthma.

Various indole derivatives are disclosed in U.S. Pat. Nos. 5,631,381 and6,630,496 B1; WO 93/25524; WO 99/43672 and WO 2004/099192.

SUMMARY OF THE INVENTION

The present invention provides, in its principal aspect, compounds ofthe general formula:

wherein

spacer is

Y is CH or N, provided that if Y is CH then n is 0-2; if Y is N then nis 2-4;if Y is CH then R¹ and R² taken together are —(CH₂)_(a)—NR¹¹—(CH₂)₂—where a is 1-2 which when taken together with Y form a piperidine orpyrrolidine ring which is optionally substituted with 1-3 groupsselected from fluoro, fluoroalkyl, (C₁-C₄)alkyl, alkoxy, aryl,(C₃-C₇)cycloalkyl, heterocycloalkyl containing 1-2 hetero atoms selectedfrom (O, S) and (C₁-C₅)alkyl-O—(C₁-C₅)alkyl; andif Y is N then R¹ and R² independently are (C₁-C₅)alkyl or(C₃-C₆)cycloalkyl, or R′ and R² taken together with the nitrogen towhich they are attached form a 5-7 member heterocyclic ring system with0-1 additional hetero atoms selected from O and S which is optionallysubstituted with 1-3 (C₁-C₅)alkyl, fluoroalkyl or (C₃-C₆)cycloalkylgroups, or R¹ and R² taken together are —(CH₂)_(a)—NR¹¹—(CH₂)₂—, where ais 2-3, which when taken together with Y form a piperazine orhomopiperazine ring which is optionally substituted with 1-3 groupsselected from fluoro, fluoroalkyl, (C₁-C₄)alkyl, alkoxy, aryl,(C₃-C₇)cycloalkyl, heterocycloalkyl containing 1-2 hetero atoms selectedfrom (O, S) and (C₁-C₅)alkyl-O—(C₁-C₅)alkyl;R³ is 0-2 of groups selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, heterocycloalkylcontaining 1-3 hetero atoms selected from (O, S) and(C₁-C₃)alkyl-O—(C₁-C₅)alkyl;R⁴ and R⁵ are selected independently from H, (C₁-C₅)alkyl,(C₁-C₈)alkoxy, (C₁-C₅)alkyl-O—(C₁-C₅)alkyl, (C₃-C₆)cycloalkyl, aryl, CF₃and halogen;R⁶ is CONR⁷R⁸, —(CH₂)_(x)—O—R⁹, alkyl, fluoroalkyl or SO₂NR⁷R⁸;x is 1-4;R⁷ and R⁸ independently are hydrogen, (C₁-C₅)alkyl or (C₃-C₆)cycloalkyl,or R⁷ and R⁸ together with the nitrogen to which they are attached forma 5-7 member heterocyclic ring system with 0-1 additional hetero atomsselected from O, S and N(R¹⁰, wherein the resulting ring is optionallysubstituted with 1-3 (C₁-C₅)alkyl or (C₃-C₆)cycloalkyl groups;R⁹ is hydrogen, (C₁-C₅)alkyl, (C₃-C₇)cycloalkyl or aryl;R¹⁰ is (C₁-C₅)alkyl, (C₁-C₈)alkoxy, (C₁-C₅)alkyl-O—(C₁-C₅)alkyl,(C₃-C₆)cycloalkyl or aryl; andR¹¹ is (C₁-C₅)alkyl, fluoroalkyl or (C₃-C₆)cycloalkyl and thepharmaceutically acceptable salts, and individual stereoisomers thereof.

This invention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier in combination with an effectiveamount of at least one compound of formula (I).

The present invention also provides a method of treating conditions inwhich modulation of histamine H₃ receptors may be of therapeuticimportance such as inflammation, migraine, motion sickness, pain,Parkinson's Disease, epilepsy, cardiovascular disease (i.e. hyper orhypotension, acute myocardial infarction), gastrointestinal disorders(acid secretion, motility) and CNS disorders involving attention orcognitive disorders (i.e., Alzheimer's, Attention Deficit Disorder,age-related memory dysfunction, stroke, etc.), psychiatric disorders(i.e., depression, schizophrenia, obsessive-compulsive disorders, etc.);sleep disorders (i.e. narcolepsy, sleep apnea, insomnia, disturbedbiological and circadian rhythms, hyper- and hyposomnolence), anddisorders such as obesity, anorexia/bulimia, thermoregulation, hormonerelease) comprising administering an effective amount of a compound offormula (I) to a patient in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION

Preferably for compounds of formula (I), R¹—Y—R² is

R³ is H; R⁴ is H; 5-methoxy, 5-fluoro or methyl; R⁵ is H; and R⁶ is—CH₂OCH₃ or —(CH₂)₂OCH₃.

Presently preferred compounds include:

-   2-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   -Methyl-1-[4-(3-piperidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Methyl-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole;-   1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   5-Methoxy-2-methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   5-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   5-Bromo-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   4-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   5-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2,5-Dimethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   6-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Methyl-5-fluoro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   1-[3-Methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole;-   1-[3-Chloro-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole;-   2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   5-Methoxy-2-methyl-1-[4-(4-pyrrolidin-1-ylbut-1-ynyl)phenyl]-1H-indole;-   (5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanone;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid cyclobutylamide;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid cyclopentylamide;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid cyclohexylamide;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid cycloheptylamide;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanone;-   2-(3-Morpholin-4-ylpropoxy)-6,7,8,9-tetrahydropyrido[1,2-a]indole;-   (1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)morpholin-4-ylmethanone;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid butylamide;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid isobutylamide;-   1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid cyclohexylmethylamide;-   5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylic    acid cyclohexylamide;-   1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2-carboxylic acid    ethyl ester;-   {1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol;-   2-Methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Cyclohexyloxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Isopropoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Cyclopentyloxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   {5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol;-   2-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;-   2-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)cyclohexyl]-1H-indole;-   2-(2-Methoxyethyl)-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;    and-   2-{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}ethanol.

Certain compounds of the invention may exist in different isomeric (e.g.enantiomers and distereoisomers) forms. The invention contemplates allsuch isomers both in pure form and in a mixture, including racemicmixtures. Enol and tautomeric forms are also included.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, e.g., hemi-hydrate. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water, ethanol, and the like are equivalent to the unsolvatedforms for the purposes of the invention.

Certain compounds of the invention also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the nitrogen atoms mayform salts with acids. Examples of suitable acids for salt formation arehydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic,salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonicand other mineral carboxylic acids well known to those in the art. Thesalts are prepared by contacting the free base form with a sufficientamount of the desired acid to produce a salt in the conventional manner.The free base forms may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous hydroxide,potassium carbonate, ammonia, and sodium bicarbonate. The free baseforms differ from their respective salt forms somewhat in certainphysical properties, such as solubility in polar solvents, but the acidsalts are equivalent to their respective free base forms for purposes ofthe invention. (See, for example S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein byreference.

As throughout this specification and appended claims, the followingterms have the meanings ascribed to them:

The term “alkyl” as used herein refers to straight or branched chainradicals derived from saturated hydrocarbons by the removal of onehydrogen atom. Representative examples of alkyl groups include methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,and the like.

The term “cycloalkyl” as used herein refers to an aliphatic ring systemhaving 3 to 10 carbon atoms and 1 to 3 rings, including, but not limitedto cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantly amongothers. Cycloalkyl groups can be unsubstituted or substituted with one,two or three substituents independently selected from lower alkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino,hydroxyl, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyland carboximide.

“Cycloalkyl” includes cis or trans forms. Furthermore, the substituentsmay either be in endo or exo positions in the bridged bicyclic systems.

The term “halo” or “halogen” as used herein refers to I, Br, Cl or F.

The term “heteroatom” as used herein refers to at least one N, O or Satom.

The term “heterocyclyl” as used herein, alone or in combination, refersto a non-aromatic 3- to 10-membered ring containing at least oneendocyclic N, O, or S atom. The heterocycle may be optionallyaryl-fused. The heterocycle may also optionally be substituted with atleast one substituent which is independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, amino, nitro,trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl,aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl among others.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients. The phrase “therapeutically effective amount” of thecompound of the invention means a sufficient amount of the compound totreat disorders, at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgment. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0001 to about 1000mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.001 to about 5 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

The compositions can also be delivered through a catheter for localdelivery at a target site, via an intracoronary stent (a tubular devicecomposed of a fine wire mesh), or via a biodegradable polymer. Thecompounds may also be complexed to ligands, such as antibodies, fortargeted delivery.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; (f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylcne glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. Prodrugs of the present invention may be rapidlytransformed in vivo to the parent compound of the above formula, forexample, by hydrolysis in blood. A thorough discussion is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of theA.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press (1987), hereby incorporated by reference.

Compounds of the present invention that are formed by in vivo conversionof a different compound that was administered to a mammal are intendedto be included within the scope of the present invention.

Compounds of the present invention may exist as stereoisomers whereinasymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The present invention contemplates various stereoisomersand mixtures thereof. Stereoisomers include enantiomers anddiastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The invention may be illustrated by the following representative schemeand examples.

Example 1 2-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

1-(4-Methoxyphenyl)-2-methyl-1H-indole.1-(4-Methoxyphenyl)-2-methyl-1H-indole was synthesized according toBuchwald et al. J. Am. Chem. Soc. 2001, 123, 7727. 2-Methylindole (157mg, 1.2 mmol), 4-iodoanisole (234 mg, 1 mmol), copper(I) iodide (2 mg,0.01 mmol), trans-1,2-diaminocyclohexane (11.4 mg, 0.1 mmol), andpotassium phosphate tribasic (446 mg, 2.1 mmol) were stirred in dioxane(1 mL) at 90° C. overnight. The reaction mixture was filtered through apad of silica and washed with ethyl acetate. SiO₂ chromatography with5-20% ethyl acetate/hexanes gave 175 mg of the desired product (74%yield). LC-MS (C₁₆H₁₅NO calc'd 237) m/z 238 (M+H).

4-(2-Methylindol-1-yl)phenol. 1-(4-Methoxyphenyl)-2-meth 4-1H-indole(175 mg, 0.73 mmol) was dissolved in dichloromethane (2 mL) and cooledto 0° C. Boron tribromide (2.19 mL, 1 M solution in dichloromethane,2.19 mmol) was added dropwise, and the reaction was stirred for 2 hours.The reaction was quenched by addition of saturated sodium bicarbonatesolution, then extracted with dichloromethane followed by ethyl acetate.The organic extracts were dried over MgSO₄ and concentrated. Thereaction was assumed to be quantitative. LC-MS (C₁₅H₁₃NO calc'd 223) m/z224 (M+H).

1-[4-(3-Chloropropoxy)phenyl]-2-methyl-1H-indole.4-(2-Methylindol-1-yl)phenol (0.36 mmol) was heated at 70° C. in2-butanone (3 mL) with 1-bromo-3-chloropropane (0.107 mL, 1.08 mmol) andpotassium carbonate (0.15 g, 1.08 mmol) overnight. The solvent wasevaporated. The resulting residue was diluted with ethyl acetate andwashed with saturated ammonium chloride solution. The aqueous layer wasback-extracted with ethyl acetate. The organic extracts were dried overMgSO₄ and concentrated. SiO₂ chromatography with 5-20% ethylacetate/hexanes gave the desired product as a colorless oil, 60 mg (56%yield, 2 steps). LC-MS (C₁₈H₁₈ClNO calc'd 299) m/z 300, 302 (M+H).

2-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole.1-[4-(3-Chloropropoxy)phenyl]-2-methyl-1H-indole (20 mg, 0.067 mmol) wasdissolved in N-methylpyrrolidinone (0.5 mL), and pyrrolidine (0.017 mL,0.2 mmol), potassium carbonate (46 mg, 0.34 mmol), and a catalyticamount of potassium iodide were added. The reaction was heated to 70° C.overnight. The reaction was diluted with saturated sodium bicarbonatesolution and extracted with ethyl acetate. The organic extracts weredried over MgSO₄ and concentrated. The residue was purified by semi-prepLC-MS to give 9.6 mg of the desired product (43% yield). LC-MS(C₂₂H₂₆N₂O calc'd 334) m/z 335 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.58-7.53 (m, 1H), 7.26-7.25 (m, 3H), 7.12-6.99 (m, 4H), 6.37 (s, 1H),4.10 (t, J=6 Hz, 2H), 2.99-2.90 (m, 6H), 2.24 (s, 3H), 2.22-2.14 (m,2H), 2.00-1.90 (m, 6H).

Example 2 2-Methyl-1-[4-(3-piperidin-1-ylpropoxy)phenyl]-1H-indole

2-Methyl-1-[4-(3-piperidin-1-ylpropoxy)phenyl]-1H-indole was synthesizedby a method analogous to that used for Example 1 using piperidine inplace of pyrrolidine in the final step. LC-MS (C₂₃H₂₈N₂O calc'd 348) m/z349 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.52 (m, 1H), 7.23-7.21 (m,3H), 7.12-6.99 (m, 4H), 6.37 (s, 1H), 4.09 (t, J=6 Hz, 2H), 2.79-2.68(m, 6H), 2.27 (s, 3H), 2.20-2.09 (m, 2H), 1.77-1.69 (m, 4H), 1.56-1.52(m, 2H).

Example 32-Methyl-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole

2-Methyl-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole wassynthesized by a method analogous to that used for Example 1 using(R)-2-methylpyrrolidine in place of pyrrolidine in the final step. LC-MS(C₂₃H₂₈N₂O calc'd 348) m/z 349 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.58-7.52 (m, 1H), 7.26-7.25 (m, 3H), 7.12-7.00 (m, 4H), 6.37 (s, 1H),4.16-4.05 (m, 2H), 3.46-3.39 (m, 1H), 3.22-3.13 (m, 1H), 2.75-2.63 (m,1H), 2.57-2.42 (m, 2H), 2.27 (s, 3H), 2.21-1.55 (m, 6H), 1.25 (d, J=6.3Hz, 3H).

Example 4 1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]4H-indole

1-[3-(4-Iodophenoxy)propyl]pyrrolidine. 4-Iodophenol (2.2 g, 10 mmol)was dissolved in N,N-dimethylformamide (30 mL) under N₂, and sodiumhydride (0.48 g, 60% dispersion in mineral oil, 12 mmol) was added inportions. 1-(3-Chloropropyl)pyrrolidine (1.77 g, 12 mmol) and sodiumiodide (1.8 g, 12 mmol) were added, and the reaction mixture was stirredat 70° C. overnight. The reaction mixture was diluted with ethyl acetateand washed with water. The ethyl acetate solution was washed with 1 NHCl (2×). The acidic extracts were made basic with 2 N NaOH, then wereextracted with ethyl acetate (2×). All ethyl acetate extracts werecombined, dried over MgSO₄ and concentrated to give a yellow oil, 2.98 g(90% crude yield). LC-MS (C₁₃H₁₈INO calc'd 331) m/z 332 (M+H).

1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]1H-indole.1-[3-(4-Iodophenoxy)propyl]-pyrrolidine (66 mg, 0.2 mmol), indole (28mg, 0.24 mmol), copper(I) iodide (0.4 mg, 0.002 mmol),trans-1,2-diaminocyclohexane (0.0024 mmol, 0.02 mmol), and potassiumphosphate tribasic (89 mg, 0.42 mmol) were stirred at 90° C. in dioxaneovernight. The reaction mixture was filtered through celite and washedwith dichloromethane. The filtrate was concentrated, and the resultingresidue was purified by semi-prep LC-MS to give 22.4 mg of the desiredproduct (35% yield). LC-MS (C₂₁H₂₄N₂O calc'd 320) m/z 321 (M+H); ¹H NMR(300 MHz, CDCl₃) δ 7.67 (d, J=6.9 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H),7.40-7.35 (m, 2H), 7.27 (d, J=3 Hz, 1H), 7.22-7.10 (m, 2H), 7.04-6.99(m, 2H), 6.64 (d, J=3 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 2.66 (t, J=7.2Hz, 2H), 2.57-2.52 (m, 4H), 2.09-2.00 (m, 2H), 1.83-1.78 (m, 41-1).

Example 55-Methoxy-2-methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Methoxy-2-methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using5-methoxy-2-methylindole in place of indole in the final step. LC-MS(C₂₃H₂₈N₂O₂ calc'd 364) m/z 365 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.23-7.20 (m, 2H), 7.03 (d, J=2.4 Hz, 1H), 7.02-6.97 (m, 2H), 6.93 (d,J=8.7 Hz, 1H), 6.72 (dd, J=9 Hz, 2.4 Hz, 1H), 6.30 (s, 1H), 4.10 (t, J=6Hz, 2H), 3.85 (s, 3H), 3.03-2.96 (m, 4H), 2.25 (s, 3H), 2.24-2.16 (m,2H), 1.99-1.94 (m, 4H).

Example 6 5-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using5-methylindole in place of indole in the final step. LC-MS (C₂₂H₂₆N₂Ocalc'd 334) m/z 335 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.46 (s, 1H),7.40-7.33 (m, 2H), 7.23 (d, J=3.3 Hz, 1H), 7.23 (d, J=3.3 Hz, 1H),7.04-6.98 (m, 2H), 6.56 (d, J=3.3 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H),2.80-2.70 (m, 6H), 2.17-2.06 (m, 2H), 1.88-1.84 (m, 4H).

Example 7 5-Bromo-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Bromo-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole was synthesizedby a method analogous to that used for Example 4 using 5-bromoindole inplace of indole in the final step. LC-MS (C₂₁H₂₃BrN₂O calc'd 399) m/z400, 402 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.79 (s, 1H), 7.37 (d, J=4.8Hz, 2H), 7.29-7.26 (m, 3H), 7.01 (d, J=8.7 Hz, 2H), 6.58 (d, J=3.3 Hz,1H), 4.09 (t, J=6.3 Hz, 2H), 2.92-2.82 (m, 6H), 2.20-2.11 (m, 2H),1.94-1.89 (m, 4H).

Example 8 4-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

4-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using4-chloroindole in place of indole in the final step. LC-MS (C₂₁H₂₃ClN₂Ocalc'd 354) m/z 355, 357 (M+H); NMR (300 MHz, CDCl₃) δ 7.39-7.30 (m,4H), 7.17-7.08 (m, 2H), 7.04-6.99 (m, 2H), 6.75 (d, J=3.3 Hz, 1H), 4.09(t, J=6 Hz, 2H), 2.97-2.89 (m, 6H), 2.22-2.13 (m, 2H), 1.96-1.92 (m,4H).

Example 9 5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using5-methoxyindole in place of indole in the final step. LC-MS (C₂₂H₂₆N₂O₂calc'd 350) m/z 351 (M+H).

Example 10 5-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using5-chlorolindole in place of indole in the final step. LC-MS (C₂₁H₂₃ClN₂Ocalc'd 354) m/z 355, 357 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J=2.1Hz, 1H), 7.37-7.32 (m, 3H), 7.28 (d, J=3 Hz, 1H), 7.14 (dd, J=8.7 Hz,1.8 Hz, 1H), 7.04-6.99 (m, 2H), 6.58 (d, J=3 Hz, 1H), 4.09 (t, J=6.3 Hz,2H), 2.83-2.73 (m, 6H), 2.16-2.07 (m, 2H), 1.90-1.85 (m, 4H).

Example 11 2,5-Dimethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2,5-Dimethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using2,5-dimethylindole in place of indole in the final step. LC-MS(C₂₃H₂₈N₂O calc'd 348) m/z 349 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.40 (s,1H), 7.23-7.19 (m, 2H), 7.04-6.99 (m, 2H), 6.95-6.90 (m, 2H), 6.28 (s,1H), 4.10 (t, J=6.3 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 2.57 (m, 4H), 2.43(s, 3H), 2.25 (s, 3H), 2.12-1.99 (m, 2H), 1.84-1.80 (m, 4H).

Example 12 6-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

6-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using6-chloroindole in place of indole in the final step. LC-MS (C₂₁H₂₃ClN₂Ocalc'd 354) m/z 355, 357 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=8.4Hz, 1H), 7.38 (s, 1H), 7.37-7.34 (m, 2H), 7.26-7.25 (m, 1H), 7.11 (dd,J=8.4 Hz, 1.8 Hz, 1H), 7.06-7.01 (m, 2H), 6.62 (d, J=3.3 Hz, 1H), 4.10(t, J=6.3 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H), 2.59 (m, 4H), 2.12-2.03 (m,2H), 1.88-1.78 (m, 4H).

Example 132-Methyl-5-fluoro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2-Methyl-5-fluoro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using5-fluoro-2-methylindole in place of indole in the final step. LC-MS(C₂₂H₂₅FN₂O calc'd 352) m/z 353 (M+14).

Example 141-[3-Methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole

1-[3-Methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole wassynthesized by a method analogous to that used for Example 4, using4-bromoguaiacol in the first step rather than 4-iodophenol and2-methylindole in the final step. LC-MS (C₂₃H₂₈N₂O₂ calcd 364) m/z 365(M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.55 (m, 1H), 7.14-7.07 (m, 3H),6.99 (d, J=8.7 Hz, 1H), 6.88 (dd, J=8.4 Hz, 2.4 Hz, 2H), 6.83 (d, J=2.4Hz, 1H), 6.38 (s, 1H), 4.17 (t, J=6.3 Hz, 2H), 3.83 (s, 3H), 3.02-2.94(m, 6H), 2.29 (s, 3H), 2.27-2.20 (m, 2H), 1.97-1.93 (m, 4H).

Example 151-[3-Chloro-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole

1-[3-Chloro-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole wassynthesized by a method analogous to that used for Example 4, using4-bromo-2-chlorophenol in the first step rather than 4-iodophenol and2-methylindole in the final step. LC-MS (C₂₂H₂₅ClN₂O calc'd 368) m/z369, 371 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.58-7.54 (m, 1H), 7.37 (d,J=2.4 Hz, 1H), 7.20 (dd, J=8.7 Hz, 2.7 Hz, 1H), 7.11-7.02 (m, 4H), 6.38(s, 1H), 4.19 (t, J=6.3 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.77 (m, 4H),2.24-2.15 (m, 2H), 1.91-1.87 (m, 4H).

Example 16 2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 4 using2-propylindole in place of indole in the final step. 2-Propylindole wasprepared according to Kuyper et al. (J. Med. Chem. 1996, 39, 892). LC-MS(C₂₄H₃₀N₂O calc'd 362) m/z 363 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.58 (m,1H), 7.25-7.21 (m, 2H), 7.12-6.99 (m, 5H), 6.38 (s, 1H), 4.10 (t, J=6Hz, 2H), 3.01-2.93 (m, 6H), 2.55 (t, J=7.8 Hz, 2H), 2.25-2.15 (m, 2H),1.98-1.91 (m, 4H), 1.66-1.54 (m, 2H), 0.91 (t, J=7.5 Hz, 3H).

Example 175-Methoxy-2-methyl-1-[4-(4-pyrrolidin-1-ylbut-1-ynyl)phenyl]-1H-indole

1-(4-Bromophenyl)-5-methoxy-2-methyl-1H-indole and1-(4-Iodophenyl)-5-methoxy-2-methyl-1H-indole. 5-Methoxy-2-methylindole(500 mg, 3.1 mmol) and 1-bromo-4-iodobenzene (877 mg, 3.1 mmol) weredissolved in toluene (6 mL). To the resulting solution were addedcopper(I) iodide (12 mg, 0.062 mmol), potassium phosphate tribasic (1.32g, 6.2 mmol), and N,N′-dimethylethylenediamine (6.6 μL, 0.062 mmol). Themixture was heated at 80° C. overnight, allowed to cool to roomtemperature and filtered through a pad of silica. The resulting solutionwas concentrated to give a mixture of both the bromo and the iodohalophenyl indoles, which were used without further purification(assumed quantitative).

4-[4-(5-Methoxy-2-methylindol-1-yl)phenyl]but-3-yn-1-ol. To a solutionof the above mixture of indoles (50 mg) in triethylamine (1 mL) wasadded copper(I) iodide (6 mg, 0.03 mmol) andtetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). After3-butyn-1-ol (15 μL, 0.20 mmol) was added, the resulting mixture washeated at 80° C. overnight. The reaction was allowed to cool and wasfiltered through a pad of silica. The silica was washed with ethylacetate. Concentration gave the desired alcohol, which was used withoutfurther purification (assumed quantitative).

5-Methoxy-2-methyl-1-[4-(4-pyrrolidin-1-ylbut-1-ynyl)phenyl]-1H-indole.To a solution of 4-[4-(5-Methoxy-2-methylindol-1-yl)phenyl]but-3-yn-1-ol(60 mg, 0.19 mmol) in methylene chloride (1 mL) at 0° C. was addedtriethylamine (54 μL, 0.39 mmol) and methanesulfonylchloride (18 μL,0.39 mmol). After the solution was stirred at 0° C. for 2 hours,pyrrolidine (163 μL, 1.95 mmol) was added and the reaction was allowedto warm to room temperature overnight. After the reaction was quenchedwith water, the organic layer was dried over MgSO₄, and concentrated.The residue was purified by HPLC to give the desired indole (2.8 mg).LC-MS (C₂₄H₂₆N₂O calc'd 358) m/z 359 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.53 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.03 (d, J=2.4 Hz, 1H),6.99 (d, J=9.0 Hz, 1H), 6.73 (dd, J=2.7, 9.0 Hz, 1H), 6.32 (s, 1H), 3.85(s, 3H), 2.92-2.83 (m, 4H), 2.76 (m, 4H), 2.28 (s, 3H), 1.88 (m, 4H).

Example 18(5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanone

1-{4-[3-(2R-Methyl-pyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid ethyl ester was synthesized by a method analogous to that used forExample 4 starting from ethyl 5-methoxyindole-2-carboxylate.1-{4-[3-(2R-Methyl-pyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid ethyl ester (0.43 mmol) was dissolved in THF (2.4 mL), methanol(1.2 mL), and water (0.4 mL), and sodium hydroxide (103 mg, 2.58 mmol)was added. The reaction mixture was heated at 50° C. overnight. A 1 Nsolution of HCl was added until the pH measured 7, and the solvents wereevaporated. A portion of the residue (ca. 0.2 mmol) was dissolved inN,N-dimethylformamide (1 mL), and pyrrolidine (0.017 mL, 0.2 mmol),PyBrOP (0.14 g, 0.3 mmol), and diisopropylethylamine (0.104 mL, 0.6mmol) were added. The reaction mixture was stirred overnight, and thenthe solvent was evaporated. The residue was purified by semi-prep LC-MSto give the desired product and a PyBrOP-related side product. Theresidue was further purified by SiO₂ chromotography with ethyl acetate,then 10% methanol/ethyl acetate, then 2% triethylamine/10%methanol/ethyl acetate to give the desired product, 15.1 mg. LC-MS(C₂₈H₃₅N₃O₃ calc'd 461) m/z 462 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.30(d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.97 (d,J=8.7 Hz, 2H), 6.88 (dd, J=9 Hz, 2.4 Hz, 1H), 6.76 (s, 1H), 4.09-4.04(m, 2H), 3.86 (s, 3H), 3.49 (t, J=6.6 Hz, 2H), 3.36 (t, J=6.2 Hz, 2H),3.22 (dt, J=2.7 Hz, 8.7 Hz, 1H), 3.07-2.98 (m, 1H), 2.36-1.65 (m, 12 H),1.51-1.39 (m, 1H), 1.12 (d, J=6 Hz, 3H).

Example 191-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclobutylamide

1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclo-butylamide was synthesized by a method analogous to that usedfor Example 18 using Cyclobutylamine in place of pyrrolidine. LC-MS(C₂₇H₃₃N₃O₂ calc'd 431) m/z 432 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.68(d, J=7.8 Hz, 1H), 7.29-7.02 (m, 8H), 5.91 (d, J=7.8 Hz, 1H), 4.51-4.37(m, 1H), 4.10 (t, J=6.3 Hz, 2H), 3.25-3.14 (m, 4H), 3.07-2.98 (m, 1H),2.40-1.60 (m, 11H), 1.51-1.38 (m, 1H), 1.12 (d, J=6 Hz, 3H).

Example 201-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclopentylamide

1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclopentylamide was synthesized by a method analogous to that usedfor Example 18 using cyclopentylamine in place of pyrrolidine. LC-MS(C₂₈H₃₅N₃O₂ calc'd 445) m/z 446 (M+H).

Example 211-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylamide

1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylamide was synthesized by a method analogous to that usedfor Example 18 using cyclohexylamine in place of pyrrolidine. LC-MS(C₂₉H₃₇N₃O₂ calc'd 459) m/z 460 (M+H).

Example 221-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cycloheptylamide

1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cycloheptylamide was synthesized by a method analogous to that usedfor Example 18 using cycloheptylamine in place of pyrrolidine. LC-MS(C₃₀H₃₉N₃O₂ calc'd 473) m/z 474 (M+H).

Example 23(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanone

(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanonewas synthesized by a method analogous to that used for Example 18. LC-MS(C₂₇H₃₃N₃O₂ calc'd 431) m/z 432 (M+H).

Example 242-(3-Morpholin-4-ylpropoxy)-6,7,8,9-tetrahydropyrido[1,2-a]indole

(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)piperidin-1-ylmethanonewas synthesized by a method analogous to that used for Example 18 usingpiperidine in place of Pyrrolidine. LC-MS (C₂₈H₃₅N₃O₂ calc'd 445) m/z446 (M+H).

Example 25(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)morpholin-4-ylmethanone

(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)morpholin-4-ylmethanonewas synthesized by a method analogous to that used for Example 18 usingmorpholine in place of pyrrolidine. LC-MS (C₂₇H₃₃N₃O₃ calc'd 447) m/z448 (M+H).

Example 26

1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid butylamide

1-{4-[3-(2-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid butylamide was synthesized by a method analogous to that used forExample 18 using butylamine in place of pyrrolidine. LC-MS (C₂₇H₃₅N₃O₂calc'd 433) m/z 434 (M+H).

Example 271-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid isobutylamide

1-{4-[3-(2-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid isobutylamide was synthesized by a method analogous to that usedfor Example 18 using isobutylamine in place of pyrrolidine. LC-MS(C₂₇H₃₅N₃O₂ calc'd 433) m/z 434 (M+H).

Example 281-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylmethylamide

1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylmethylamide was synthesized by a method analogous to thatused for Example 18 using cyclohexylmethylamine in place of pyrrolidine.LC-MS (C₃₀H₃₉N₃O₂ calc'd 473) m/z 474 (M+H).

Example 295-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylamide

5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylamide was synthesized by a method analogous to that usedfor Example 18 using cyclohexylamine in place of pyrrolidine. LC-MS(C₃₀H₃₉N₃O₃ calc'd 489) m/z 490 (M+H).

Example 30 1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2-carboxylicacid ethyl ester

1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2-carboxylic acid ethylester was synthesized by a method analogous to that used for Example 4starting from ethyl indole-2-carboxylate. LC-MS (C₂₄H₂₈N₂O₃ calc'd 392)m/z 393 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J=7.8 Hz, 1H), 7.43(s, 1H), 7.29-7.15 (m, 4H), 7.06 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.7 Hz,2H), 4.23 (q, J=7.2 Hz, 2H), 4.10 (t, J=6 Hz, 2H), 3.06-3.01 (m, 4H),2.27-2.17 (m. 2H), 2.01-1.96 (m, 6H), 1.26 (t, J=7.2 Hz, 3H).

Example 31{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol

(1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2-carboxylic acidethyl ester (0.5 g, 1.27 mmol) was dissolved in THF (10 mL) and addeddropwise to lithium aluminum hydride (1.53 mL, 1 M solution in THF, 1.53mmol) in THF (10 mL). The reaction was stirred at 60° C. for 2 hours.Water (0.3 mL), 2 N NaOH (0.3 mL), and water (0.9 mL) were added, andthe solvent was evaporated. The resulting residue was diluted with waterand extracted with dichloromethane. The dichloromethane extracts weredried over MgSO₄ and concentrated to give a white solid, 0.36 g. A smallamount of the product was purified by semi-prep LC-MS to give 3.5 mg ofpure desired product. LC-MS (C₂₂H₂₆N₂O₂ calc'd 350) m/z 351 (M+H); ¹HNMR (300 MHz, CDCl₃) δ 7.65-7.61 (m, 1H), 7.35 (d, J=8.7 Hz, 2H),7.16-7.08 (m, 3H), 7.01 (d, J=8.7 Hz, 2H), 6.65 (s, 1H), 4.64 (s, 2H),4.10 (t, J=6 Hz, 2H), 2.93-2.86 (m, 6H), 2.21-2.12 (m, 2H), 1.94-1.90(m, 4H).

Example 322-Methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol (15 mg)was dissolved in a mixture of methanol, acetonitrile, and 1 N HCl. Afterstanding at room temperature for 2 hours, the solution was purified bysemi-prep LC-MS to give 1.1 mg of the desired product. LC-MS (C₂₃H₂₈N₂O₂calc'd 364) m/z 365 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.66-7.61 (m, 1H),7.33 (d, J=9 Hz, 2H), 7.20-6.75 (m, 5H), 6.66 (s, 1H), 4.40 (s, 2H),4.10 (t, J=6.3 Hz, 2H), 3.28 (s, 3H), 2.82-2.71 (m, 6H), 2.17-2.08 (m,2H), 1.87 (m, 4H).

Example 332-Cyclohexyloxymethyl-1-[4-(3-pyrrolidin-4-ylpropoxy)phenyl]-1H-indole

2-Cyclohexyloxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indolewas synthesized by a method analogous to that used for Example 32 usingcyclohexanol in place of methanol. LC-MS (C₂₈H₃₆N₂O₂ calc'd 432) m/z 433(M+H).

Example 342-Isopropoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2-Isopropoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 32 usingisopropanol in place of methanol. LC-MS (C₂₅H₃₂N₂O₂ calc'd 392) m/z 393(M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.63-7.61 (m, 1H), 7.35-7.32 (m, 2H),7.14-7.07 (m, 3H), 7.01 (d, J=8.7 Hz, 2H), 6.64 (s, 1H), 4.42 (s, 2H),4.10 (t, J=6.3 Hz, 2H), 3.58-3.48 (m, 1H), 2.76-2.38 (m, 6H), 2.08-2.02(m, 2H), 1.83-1.71 (m, 4H), 1.08 (d, J=6 Hz, 6H).

Example 352-Cyclapentyloxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2-Cyclopentyloxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indolewas synthesized by a method analogous to that used for Example 32 usingcyclopentanol in place of methanol. LC-MS (C₂₇H₃₄N₂O₂ calc'd 418) m/z419 (M+H).

Example 36

{5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol

{5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanolwas synthesized by a method analogous to that used for Example 31starting with ethyl 5-methoxyindole-2-carboxylate. LC-MS (C₂₃H₂₈N₂O₃calc'd 380) m/z 381 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d, 0.1=8.1Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=8.4 Hz, 3H), 6.80 (d, J=8.7 Hz, 1H),6.56 (s, H), 4.61 (s, 2H), 4.07 (m, 2H), 3.85 (s, 3H), 2.83 (m, 6H),2.14 (m, 2H), 1.91 (m, 4H).

Example 372-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

N-(2-Iodophenyl)acetamide. 2-Iodoaniline (1.00 g, 4.56 mmol) wasdissolved in pyridine (5 mL) and cooled to 0° C. After acetyl chloride(314 μL, 5.94 mmol) was added, the reaction was stirred at 0° C. for 1hour and then at room temperature for 2 hours. The reaction was dilutedwith 1 N HCl and extracted with ether. The organic layer was dried(MgSO₄) and concentrated to give the desired acetamide (assumedquantitative), which was used in the next reaction without furtherpurification.

2-Cyclopropyl-1H-indole. To a solution of N-(2-iodophenyl)acetamide (100mg, 0.38 mmol) in dioxane (750 mL) and 1,1,3,3-tetramethylguanidine (750mL) was added cyclopropylacetylene (41 mL, 0.49 mmol),bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol), andcopper(I) iodide (10 mg, 0.05 mmol). The reaction was stirred overnightat 80° C. The solution was cooled and partitioned between water andmethylene chloride. The organic layer was dried (MgSO₄) and concentratedto give the uncyclized Sonagashira coupling product. Dioxane (750 mL)and 1,1,3,3-tetramethylguanidine (750 mL) were added and the reactionwas stirred overnight at 90° C. The solution was again partitionedbetween water and methylene chloride. The organic layer was dried(MgSO₄) and concentrated to give the desired indole, which was usedwithout further purification.

2-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole. To asolution of 2-cyclopropyl-1H-indole (17 mg, 0.11 mmol) and1-[3-(4-iodophenoxy)propyl]pyrrolidine (36 mg. 0.11 mmol) in toluene(0.2 mL) was added copper iodide (0.2 mg), potassium phosphate (47 mg,0.22 mmol), and N,N-dimethylethylenediamine (1.2 μL, 0.11 mmol). Thereaction was stirred at 100° C. overnight. After cooling to roomtemperature, the reaction was filtered through a pad of silica. Thereaction was concentrated and purified by preparative HPLC to give 1.6mg of the desired indole. LC-MS (C₂₄H₂₈N₂O calc'd 360) m/z 361 (M+H); ¹HNMR (300 MHz, CDCl₃) δ 7.55-7.52 (m, 1H), 7.35-7.32 (m, 2H), 7.10-7.02(m, 5H), 6.16 (s, 1H), 4.11 (t, J=6.3 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H),2.59 (m, 4H), 2.08 (quint, J=7.0 Hz, 1H), 1.83 (m, 2H), 1.64 (m, 4H),0.88-0.81 (m, 2H), 0.79-0.73 (m, 2H).

Example 38 2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole wassynthesized by a method analogous to that used for Example 37 using1-pentyne in the second step. LC-MS (C₂₄H₃₀N₂O calc'd 362) m/z 363(M+H); ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.54 (m, 1H), 7.25-7.21 (m, 2H),7.09-6.99 (m, 5H), 6.38 (s, 1H), 4.10 (t, J=6 Hz, 2H), 3.01-2.93 (m,6H), 2.55 (t, J=7.8 Hz, 2H), 2.25-2.15 (m, 2H), 1.98-1.93 (m, 4H), 1.60(sextet, J=7.5 Hz, 2H), 0.91 (t, J=7.5 Hz, 3H).

Example 392-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)cyclohexyl]-1H-indole

4-(tert-Butyldimethylsilanyloxy)cyclohexanone. Synthesized by literatureprocedure. Carreño, M. C.; Urbana, A.; Di Vitta C. J. Org. Chem. 1998,63, 8320.

[4-(tert-Butyldimethylsilanyloxy)cyclohexyl]-(2-iodophenyl)amine. To asolution of 2-iodoaniline (2.5 g, 10.9 mmol) in dichloromethane (160 mL)was added 4-(tert-butyldimethylsilanyloxy)cyclohexanone (2.39 g, 10.9mmol) and acetic acid (8 mL). After the reaction was stirred for 1 hourat room temperature, sodium triacetoxyborohydride (3.47 g, 16.4 mmol)was added and the reaction was stirred at room temperature overnight.The reaction was quenched with saturated sodium bicarbonate andextracted with dichloromethane. The organic solution was dried (MgSO₄)and concentrated to give 4.47 g of the desired amine, which was usedwithout further purification. LC-MS (C₁₅H₃₀INOSi calc'd 431) m/z 432(M+H).

[4-(tert-Butyldimethylsilanyloxy)cyclohexyl]-(2-cyclopropylethynylphenyl)amine.To a solution of[4-(tert-butyldimethylsilanyloxy)cyclohexyl]-(2-iodophenyl)amine (4.47g, 10.4 mmol) in triethylamine (70 mL) was added copper(I) iodide (198mg, 1.04 mmol), followed by bis(triphenylphosphine)palladium(II)chloride (730 mg, 1.04 mmol) and cyclopropylacetylene (1.73 mL, 20.8mmol). The reaction was stirred under nitrogen at room temperatureovernight. After the reaction mixture was concentrated, the residue wasdissolved in ether and filtered through Celite. Concentration gave thecrude product, which was used without further purification inquantitative yield. LC-MS (C₂₃H₃₅NOSi calc'd 369) m/z 370 (M+H).

1-[4-(tert-Butyldimethylsilanyloxy)cyclohexyl]-2-cyclopropyl-1H-indole.To a solution of[4-(tert-butyldimethylsilanyloxy)cyclohexyl]-(2-cyclopropylethynylphenyl)amine(3.84 g, 10.4 mmol) in N,N-dimethylformamide (60 mL) was added copper(I)iodide (100 mg, 0.525 mmol). After the reaction was refluxed for 48hours, it was allowed to cool to room temperature, and the solvent wasremoved in vacuo. The residue was partitioned between water anddichloromethane. The dichloromethane was dried (MgSO₄) and concentratedto give a dark residue that was used in the next step with no furtherpurification. LC-MS (C₂₃H₃₅NOSi calc'd 369) m/z 370 (M+H).

4-(2-Cyclopropylindol-1-yl)cyclohexanol. Crude1-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]-2-cyclopropyl-1H-indolefrom above (10.4 mmol) was dissolved in tetrahydrofuran (150 mL), andtetrabutylammonium fluoride (21 mL, 1 M in THF, 21 mmol) was added.After the reaction was stirred for 72 hours it was concentrated and theresidue partitioned between ethyl acetate and water. The organic layerwas dried (MgSO₄), concentrated and purified by SiO₂ chromatography(10-50% ethyl acetate/hexanes) to give two (cis/trans) isomers (355 mgof the more polar isomer, 681 mg of the less polar isomer) of thedesired alcohol. LC-MS (C₁₇H₂₁NO calc'd 255) m/z 256 (M+H).

2-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)cyclohexyl]-1H-indole. To asolution of 4-(2-cyclopropylindol-1-yl)cyclohexanol (25 mg, 0.098 mmol,more polar isomer) in N,N′-dimethylformamide (2 mL) was added sodiumiodide (8 mg) and sodium hydride (6 mg, 60% dispersion in mineral oil,0.15 mmol). After the reaction was allowed to stir at room temperaturefor 5 minutes, 1-(3-chloropropyl)pyrrolidine (22 mg, 0.15 mmol,) wasadded, and the reaction was stirred at 85° C. for 3 hours. The reactionwas allowed to cool to room temperature and partitioned between waterand dichloromethane. The organic layer was dried (MgSO₄), andconcentrated. The residue was purified by preparative LCMS to give 8.0mg of the desired amine. ¹H NMR (300 MHz, CDCl₃) δ 7.50 (d, J=7.2 Hz,1H), 7.42 (d, J=8.1 Hz, 1H), 7.12-6.99 (m, 2H), 6.14 (s, 1H), 4.64-4.53(m, 3H), 3.58 (t, J=6.2 Hz, 2H), 3.42 (tt, J=3.9, 10.8 Hz, 1H),2.91-2.82 (m, 4H), 2.42 (m, 2H), 2.24 (m, 2H), 2.00-1.79 (m, 9H), 1.45(m, 2H), 0.95 (m, 2H), 0.74 (m, 2H); LC-MS (C₂₄H₃₄N₂O calc'd 366) m/z367 (M+H).

Spectral data for the product formed from the less polar isomer of4-(2-cyclopropylindol-1-yl)cyclohexanol:

¹H NMR (300 MHz, CDCl₃) δ 7.56-7.48 (m, 2H), 7.10-6.96 (m, 2H), 6.12 (s,1H), 4.58 (tt, J=4.2, 12.6 Hz, 1H), 3.65 (s, 1H), 3.55 (t, J=6.0 Hz,2H), 2.78-2.62 (m, 7H), 2.15 (d, J=14.7 Hz, 2H), 2.00-1.83 (m, 8H),1.69-1.25 (m, 4H), 0.984-0.873 (m, 2H), 0.764-0.713 (m, 2H); LC-MS(C₂₄H₃₄N₂O calc'd 366) m/z 367 (M+H).

Example 402-(2-Methoxyethyl)-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

2-[4-(tert-Butyldimethylsilanyloxy)but-1-ynyl]phenylamine. 2-Iodoaniline(1.76 g, 8 mmol) was dissolved in triethylamine (50 mL) and placed underN₂. tert-Butylbut-3-ynyloxydimethylsilane (2.58 g, 14 mmol) was added,followed by bis(triphenylphosphine)palladium(II) chloride (30 mg, 0.042mmol) and copper(I) iodide (7 mg, 0.036 mmol), and the reaction wasstirred overnight at room temperature. Triethylamine was evaporated, andthe residue was diluted with ether and filtered through Celite. Thefiltrate was concentrated, and the residue was purified by SiO₂chromatography (5-20% ethyl acetate/hexanes) to give the desiredproduct. The reaction was assumed to be quantitative.

2-[2-(tent-Butyldimethylsilanyloxy)ethyl]-1H-indole.2-[4-(tert-Butyldimethylsilanyloxy)but-1-ynyl]phenylamine (8 mmol) washeated at reflux in N,N-dimethylformamide (30 mL) with copper(I) iodide(5 mg, 0.026 mmol) for 3 hours. The solvent was evaporated, and theresidue was diluted with ether and filtered through Celite. The filtratewas concentrated, and the residue was purified by SiO₂ chromatography(5-20% ethyl acetate/hexanes) to give the desired product, 0.88 g. ¹HNMR (300 MHz, CDCl₃) δ8.62 (br, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.27 (d,J=7.8 Hz, 1H), 7.13-7.03 (m, 2H), 6.22 (s, 1H), 3.92 (t, J=5.7 Hz, 2H),2.95 (t, J=5.7 Hz, 2H), 0.95 (s, 9H), 0.08 (s, 6H).

1-(4-Benzyloxyphenyl)-2-[2-(tert-butyldimethylsilanyloxy)ethyl]-1H-indole.2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1H-indole (0.44 g, 1.6 mmol)and (4-benzyloxy)iodobenzene (0.6 g, 1.92 mmol) were dissolved intoluene (1.6 mL), and N,N-dimethylethylenediamine (0.034 mL, 0.32 mmol),copper(I) iodide (16 mg, 0.08 mmol), and potassium phosphate (0.72 g,3.36 mmol) were added. The mixture was heated at 100° C. overnight, thenfiltered through a plug of silica with ether. The filtrate wasconcentrated, and the residue was purified by SiO₂ chromatography (0-10%ethyl acetate/hexanes) to give the desired product, 0.62 g. LC-MS(C₂₉H₃₅NO₂Si calc'd 457) m/z 458 (M+H).

2-[1-(4-Benzyloxyphenyl)-1H-indol-2-yl]ethanol.1-(4-Benzyloxyphenyl)-2-[2-(tert-butyldimethylsilanyloxy)ethyl]-1H-indole(0.62 mmol, 1.35 mmol) was dissolved in tetrahydrofuran (6 mL) under N₂,and tetrabutylammonium fluoride (1.49 mL, 1 M in tetrahydrofuran, 1.49mmol) was added. The reaction was stirred for 2 hours, then quenchedwith saturated ammonium acetate. The mixture was extracted with ethylacetate, dried over MgSO₄, and concentrated. The residue was passedthrough a plug of silica with ethyl acetate. The filtrate wasconcentrated to give the desired product. The reaction was assumed to bequantitative. LC-MS (C₂₃H₂₁NO₂ calc'd 343) m/z 344 (M+H).

1-(4-Benzyloxyphenyl)-2-(2-methoxyethyl)-1H-indole.2-[1-(4-Benzyloxyphenyl)-1H-indol-2-yl]ethanol (0.675 mmol) wasdissolved in tetrahydrofuran (5 mL) under N₂, and sodium hydride (81 mg,60% dispersion in mineral oil, 2.03 mmol) was added. The reaction washeated to reflux, at which time iodomethane (0.42 mL, 6.75 mmol) wasadded. The reaction was stirred at reflux for 3 hours, then carefullyquenched with water. The mixture was extracted with ethyl acetate, driedover MgSO₄, and concentrated. The residue was purified by SiO₂chromatography (5-20% ethyl acetate/hexanes) to give the desiredproduct, 0.14 g. LC-MS (C₂₄H₂₃NO₂ calc'd 357) m/z 358 (M+H).

4-[2-(2-Methoxyethyl)indol-1-yl]phenol.1-(4-Benzyloxyphenyl)-2-(2-methoxyethyl)-1H-indole (0.14 g, 0.39 mmol)was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL). A catalyticamount of palladium on carbon (wet, 10% dry basis) was added, and theflask was purged with N₂ and H₂. The reaction was stirred under 1 atm ofH₂ overnight. The mixture was filtered through Celite, and the filtratewas concentrated to give the desired product. The reaction was assumedto be quantitative. LC-MS (C₁₇H₁₇NO₂ calc'd 267) m/z 266 (M−H).

2-(2-Methoxyethyl)-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole.4-[2-(2-Methoxyethyl)indol-1-yl]phenol (0.39 mmol) was dissolved inN,N-dimethylformamide (4 mL), and 1-(3-chloropropyl)pyrrolidine (58 mg,0.39 mmol), sodium hydride (19 mg, 60% dispersion in mineral oil, 0.47mmol), and sodium iodide (59 mg, 0.39 mmol) were added. The reaction washeated at 70° C. for 1.5 hours, then carefully quenched with saturatedsodium bicarbonate solution. The mixture was extracted with ethylacetate, dried over MgSO₄ and concentrated. The residue was purified bySiO₂ chromatography to give 70 mg of the desired product. LC-MS(C₂₄H₃₀N₂O₂ calc'd 378) m/z 379 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.60-7.56 (m, 1H), 7.25-7.21 (m, 2H), 7.10-7.00 (m, 5H), 6.45 (s, 1H),4.11 (t, J=6.3 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.30 (s, 3H), 2.89 (t,J=7.2 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.65 (m, 4H), 2.16-2.05 (m, 2H),1.90-1.81 (m, 4H).

Example 412-{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}ethanol

2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole.2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1H-indole (0.11 g, 0.4 mmol)and 1-[3-(4-Iodophenoxy)propyl]pyrrolidine (0.16 g, 0.48 mmol) weredissolved in toluene (0.4 mL), and N,N-dimethylethylenediamine (0.017mL, 0.16 mmol), copper(I) iodide (30 mg, 0.16 mmol), and potassiumphosphate (0.18 g, 0.84 mmol) were added. The reaction was heated at100° C. overnight. The mixture was filtered through Celite withdichloromethane. The filtrate was concentrated, and taken forwardwithout purification (crude product contains some starting material).LC-MS (C₂₉H₄₂N₂O₂Si calc'd 478) m/z 479 (M+H).

2-{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}ethanol.2-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole(0.4 mmol) was dissolved in tetrahydrofuran (2 mL) under N₂, andtetrabutylammonium fluoride (0.44 mL, 1 M in tetrahydrofuran, 0.44 mmol)was added. The reaction was stirred at room temperature for 3 hours,then quenched with saturated ammonium chloride. The mixture was dilutedwith saturated sodium bicarbonate solution and extracted with ethylacetate. The organic extracts were dried over MgSO₄ and concentrated.The residue was purified by semi-prep LC-MS to give the desired product,15.8 mg. LC-MS (C₂₃H₂₈N₂O₂ calc'd 364) m/z 365 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 7.61-7.59 (m, 1H), 7.24-7.20 (m, 2H), 7.13-7.07 (m, 2H),7.03-7.00 (m, 3H), 6.48 (s, 1H), 4.09 (t, J=6.3 Hz, 2H), 3.75 (t, J=6.6Hz, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 2.60-2.49 (m,4H), 2.10-2.01 (m, 2H), 1.85-1.76 (m, 4H).

Example 425-Methoxy-2-methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

1-(4-Benzyloxyphenyl)-5-methoxy-1H-indole-2-carboxylic acid ethyl ester.5-Methoxyindole-2-ethyl ester (0.59 g, 2.7 mmol),1-benzyloxy-4-iodobenzene (1 g, 3.23 mmol), N,N-dimethylethylenediamine(0.057 mL, 0.54 mmol), copper(I) iodide (0.1 g, 0.54 mmol), andpotassium phosphate tribasic (1.2 g, 5.67 mmol) were heated in tolueneat 100° C. for 24 hours. The mixture was filtered through a plug ofsilica with ethyl acetate, and the filtrate was concentrated. SiO₂chromatography with 5-20% ethyl acetate/hexanes gave the desired product(0.51 g, 57% yield), along with some mixed fractions (0.36 g) that weresaved for future purification. LC-MS (C₂₅H₂₃NO₄ calc'd 401) m/z 402(M+H).

[1-(4-Benzyloxyphenyl)-5-methoxy-1H-indol-2-yl]methanol. Lithiumaluminum hydride (1.53 mL, 1 M in tetrahydrofuran, 1.53 mmol) wasdiluted with tetrahydrofuran (5 mL) under N₂, and1-(4-benzyloxyphenyl)-5-methoxy-1H-indole-2-carboxylic acid ethyl ester(0.51 g, 1.27 mmol) in tetrahydrofuran (5 mL) was added dropwise. Thereaction was stirred at reflux for 2 hours, then cooled to roomtemperature. Water (0.3 mL) was added carefully, followed by 2 N NaOH(0.3 mL) and water (0.9 mL). The solvent was evaporated, and the residuewas partitioned between water and ethyl acetate. The organic wasseparated, dried over MgSO₄, and concentrated to give 0.41 g (88% yield)of crude product. LC-MS (C₂₃H₂₁NO₃ calc'd 359) m/z 360 (M+H).

1-(4-Benzyloxyphenyl)-5-methoxy-2-methoxymethyl-1H-indole.[1-(4-Benzyloxyphenyl)-5-methoxy-1H-indol-2-yl]methanol (0.2 g, 0.56mmol) was dissolved in acetonitrile (2 mL), and iodomethane (0.35 mL,5.6 mmol) and silver(I) oxide (0.39 g, 1.68 mmol) were added. Themixture was stirred overnight at 40° C., then cooled to room temperatureand filtered through a pad of Celite. The filtrate was concentrated.SiO₂ chromatography with 3-50% ethyl acetate/hexanes gave 0.16 g (77%yield) of the desired product. LC-MS (C₂₄H₂₃NO₃ calc'd 373) m/z 374(M+H).

4-(5-Methoxy-2-methoxymethylindol-1-yl)phenol.1-(4-Benzyloxyphenyl)-5-methoxy-2-methoxymethyl-1H-indole (0.16 g, 0.43mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (1 mL).Palladium on carbon (0.32 g, 10% wet) and ammonium formate (0.14 g, 2.14mmol) were added, and the reaction was stirred at reflux for 2 hours.The mixture was cooled to room temperature and filtered through a pad ofCelite. The filtrate was concentrated, and the crude material taken onwithout purification. LC-MS (C₁₇H₁₇NO₃ calc'd 283) m/z 284 (M+H).

5-Methoxy-2-methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole.4-(5-Methoxy-2-methoxymethylindol-1-yl)phenol (0.43 mmol) was dissolvedin N,N-dimethylformamide under N₂. 1-(3-Chloropropyl)pyrrolidine (74 mg,0.5 mmol), sodium hydride (20 mg, 60% wt dispersion in mineral oil, 0.5mmol) and sodium iodide (75 mg, 0.5 mmol) were added, and the mixturewas heated at 70° C. for 2 hours. The reaction was cooled to roomtemperature, diluted with water, and extracted with ethyl acetate. Theorganic extracts were dried over MgSO₄ and concentrated. Purification bysemi-prep LC-MS gave the desired product, 67.4 mg (40% yield, 2 steps).LC-MS (C₂₄H₃₀N₂O₃ calc'd 394) m/z 395 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.34-7.29 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 7.04-6.98 (m, 3H), 6.82 (d,J=2.4 Hz, 1H), 6.58 (s, 1H), 4.37 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 2H),3.86 (s, 3H), 3.28 (s, 3H), 2.69-2.64 (m, 2H), 2.58-2.54 (m, 4H),2.11-2.01 (m, 2H), 1.83-1.79 (m, 4H).

Example 435-Methyl-2-methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Methyl-2-methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indolewas synthesized by a method analogous to that used for Example 42. LC-MS(C₂₄H₃₀N₂O₂ calc'd 378) m/z 379 (M+H); ¹H NMR (300 MHz, CDCl₃) δ7.42-7.41 (m, 1H), 7.34-7.29 (m, 2H), 7.04-6.95 (m, 4H), 6.57 (s, 1H),4.38 (s, 2H), 4.09 (t, J=6.3 Hz, 2H), 3.27 (s, 3H), 2.69-2.64 (m, 2H),2.58-2.53 (m, 4H), 2.44 (s, 3H), 2.10-2.01 (m, 2H), 1.83-1.79 (m, 4H).

Example 445-Fluoro-2-methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole

5-Fluoro-2-methoxymethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole was synthesized by a method analogous to that usedfor Example 42. LC-MS (C₂₃H₂₇FN₂O₂ calc'd 382) m/z 383 (M+H); ¹H NMR(300 MHz, CDCl₃) δ 7.34-7.24 (m, 3H), 7.03-6.99 (m, 3H), 6.88 (td, J=9Hz, 2.4 Hz, 1H), 6.61 (s, 1H), 4.36 (s, 2H), 4.10 (t, J=6.3 Hz, 2H),3.28 (s, 3H), 2.69-2.64 (m, 2H), 2.57-2.53 (m, 4H), 2.10-2.01 (m, 2H),1.83-1.79 (m, 4H).

Representative compounds of the present invention that were prepared bythe procedures of Examples 1-41 were evaluated in binding assays againstcells expressing human H₃ receptor by the following procedure.

Cell Culture

Materials

[¹²⁵I]iodoproxyfan (2000 Ci/mmol) was obtained from Amersham BiosciencePiscataway, N.J.). [³H]Nα-methyhistamine (85 Ci/mmmol) was purchasedfrom Perkin Elmers Life Science (Boston, Mass.). Calcium 3 dye kit wasfrom Molecular Devices (Sunnyvale, Calif.). All other chemicals wereeither from Sigma-Aldrich (St. Louis, Mo.) or Tocris Cookson Inc.(Ellisville, Mo.).

RAGE Methodology

The human histamine H3 receptor was stably expressed in HT1080 cellscontaining the chimeric G-protein, Gq□i5 (Coward et al., Anal Biochem1999; 270:242-8). HT1080-Gqαi5 cells were grown in alpha-modified MEMcontaining 10% fetal bovine serum and 7 μg/ml blasticidin at 37° C. in5% CO₂/95% atmosphere. Cells (4.8×10⁹) were irradiated with 50 rads froma ¹³⁷Cs source and the pFG8-HH3 RAGE (Random Activation of GeneExpression; see Harrington et al., Nature Biotechnology. 2001;19:440-45) vector was subsequently integrated into the cells viaelectroporation (250V, 600 μF, 50Ω). The RAGE vector pFG8-HH3 containedcDNA sequence coding for the first exon (83 amino acids) of human H3receptor. After electroporation, cells were plated in T75 flasks andgrown in alpha-modified MEM. The culture medium was replaced 48 hoursafter electroporation with alpha-modified MEM, 10% fetal bovine serum,500 μg/ml hygromycin B and 3 μg/ml puromycin. Medium was replaced everyfour days during cell expansion. To identify RAGE activated cellsexpressing the H3 receptor, pools of approximately 10,000 colonies(5×10⁷-1.5×10⁸ cells total) were screened by PCR for the desired geneproduct (using primers specific to the RAGE vector and exon 2 of the H3receptor). Pools that were found to contain the appropriate transcript,as confirmed by sequencing, were subcloned into pools of 100 cells/well.Positive 100 cells/well pools were identified by PCR, confirmed bysequencing, and subsequently subcloned to 0.8 cells/well. Once clonesexpressing the H3 receptor were identified by PCR analysis, assays(FLIPR or radioligand binding) were performed to confirm that theactivated gene produced functional protein. The protein expression inthe initial clones obtained from the RAGE library was increased bygrowth in the presence of methotrexate. Since the integrated RAGE vectorcontains the DHFR gene, such treatment selects for cells that haveamplified the genetic locus containing the RAGE insert. Subclonesobtained after methotrexate amplification were tested for functionalactivity in FLIPR assays to identify the clone that was most suitablefor HTS. The final HT1080-Gqαi5 RAGE clone (RAGE-H3) expressing thehuman histamine H3 receptor was grown in alpha-modified MEM containing10% fetal bovine serum, 3 μg/ml puromycin, 500 μg/ml hygromycin B, 3.2μM methotrexate at 37° C. in 5% CO₂/95% atmosphere.

Membrane Preparation

RAGE-H3 cells (10⁹) were washed twice with cold PBS, scraped off theplates, and centrifuged at 1000×g for 5 minutes. Cells were resuspendedin ice-cold 10 mM Tris HCl, pH 7.4, containing 5 mM EDTA and proteaseinhibitor cocktail tablets (Roche Molecular Biochemicals). Afterincubating on ice for 10 minutes, the cells were homogenized with adounce homogenizer or a polytron tissue grinder, and centrifuged at1000×g for 10 minutes at 4° C. The resulting supernatant was centrifugedat 32,000×g for 30 minutes at 4° C. The membrane pellets wereresuspended in 50 mM Tris HCl, pH 7.4, and stored at −80° C. until use.Protein concentration was determined by the Bradford method (Bio-RadLaboratories, CA).

Radioligand Binding Assays

Binding assays were carried out in 96-well polypropylene plates in 50 mMTris HCl, pH 7.4, containing 1 mM EDTA. Reaction mixtures contained 100μl of membrane suspension, 50 of 4% DMSO, and 50 μl of increasingamounts of [¹²⁵I]iodoproxyfan (final concentration 0.0005-1.8 nM forhuman H3 receptor saturation binding assay). Nonspecific binding wasdefined by adding 10 μM clobenpropit to the reaction mixtures.Competition binding assays were performed in a reaction mixturecontaining 100 μl of membrane suspension (˜20 μg of protein/well), 50 μlof [¹²⁵I]iodoproxyfan (final concentration of ˜0.15 nM) and 50 μl oftest compound. Compounds were dissolved in DMSO and then diluted with 4%DMSO; the final maximal DMSO concentration in the binding assays was 1%.Incubations were performed for 1.5 hours at room temperature andreactions were terminated by rapid filtration over glass fiber GF/Cfilters (Perkin Elmer, MA) using a Brandel cell harvester. The filterswere presoaked in 0.3% polyethyleneimine for 30 minutes and were washedwith 500 ml of ice-cold 50 mM Tris HCl, pH 7.4, The filters were dried,impregnated with Meltilex wax scintillate (Perkin Elmer, MA) and countedwith a Betaplate scintillation counter (Perkin Elmer, MA).

Calcium Mobilization Assays

RAGE-H3 or HT1080-mH3 cells were seeded in black 384-well plates andincubated overnight at 37° C. in a 5% CO₂/95% atmosphere. After removingmedium, cells were treated with CsCl Ringer's buffer (136 mM CsCl, 5.4mM KCl, 5.5 mM D-Glucose, 20 mM Hepes, pH 7.4, 2.1 mM MgCl₂, 1.2 mMCaCl₂) containing the Calcium 3 dye (Molecular Device, CA) andprobenecid (3.75 mM) for 60 minutes, according to manufacture'sinstruction. Compounds were diluted in CsCl Ringer's buffer containing0.2% bovine serum albumin and 1.0% DMSO. The dose response of(R)-α-methylhistamine-stimulated Ca²⁺ flux was measured on aFluorometric Imaging Plate Reader (FLIPR, Molecular Devices, CA) and theconcentration of (R)-α-methylhistamine to stimulate 75% of maximumresponse was used to test the inhibitory effect of compounds.

Data Analysis

All data were analyzed by nonlinear least squares curve fitting usingPrism 4.0 software. The K_(D) and B_(max) for [¹²⁵I]iodoproxyfan werederived from the equation RL=R_(t)L/(K_(D)+L), where RL is concentrationof receptor-bound ligand at equilibrium, L is the free ligandconcentration, and R_(t) is the total receptor concentration (i.e.,B_(max)). For competition binding experiments, IC₅₀ values (theconcentration of compound producing 50% inhibition of specific binding)and Hill Coefficients (nH) were derived from fitting the data to a4-parameter logistic equation. Apparent K_(i) values were calculatedusing the Cheng-Prussof equation of K_(i)=IC₅₀/(1+(L/K_(D))), where L isthe ligand concentration. Agonist stimulation and antagonist inhibitionin FLIPR were fitted to sigmoidal dose response curves using theequation Y=Bottom+(Top−Bottom)/(1+10^(LogEC₅₀−X)), where X is thelogarithm of concentration of compounds and Y is the fluorescentresponse. Z′ values [15] were derived to evaluate the quality of theassays. Figures are representative of two to three separate experimentsperformed in triplicates or quadruplicates.

The results of this assay are set forth in the following Table 1.

TABLE 1 Selected Examples Human H3 Chemical Name (uM)2-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- K_(i) < 0.01 indoleExample 1 2-Methyl-1-[4-(3-piperidin-1-ylpropoxy)phenyl]-1H- K_(i) <0.01 indole Example 2 2-Methyl-1-{4-[3-(2R-methylpyrrolidin-1- K_(i) <0.01 yl)propoxy]phenyl}-1H-indole Example 31-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole IC₅₀ < 0.1 Example 45-Methoxy-2-methyl-1-[4-(3-pyrrolidin-1- IC₅₀ < 0.1ylpropoxy)phenyl]-1H-indole Example 55-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- IC₅₀ < 1 indoleExample 6 5-Bromo-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- IC₅₀ < 1indole Example 7 4-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-IC₅₀ < 1 indole Example 85-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- IC₅₀ < 1 indoleExample 9 5-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- IC₅₀ < 1indole Example 10 2,5-Dimethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-K_(i) < 0.1 1H-indole Example 116-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- K_(i) < 0.1 indoleExample 12 2-Methyl-5-fluoro-1-[4-(3-pyrrolidin-1- K_(i) < 0.01ylpropoxy)phenyl]-1H-indole Example 131-[3-Methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2- IC₅₀ < 1methyl-1H-indole Example 141-[3-Chloro-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2- IC₅₀ < 1methyl-1H-indole Example 152-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- K_(i) < 0.01 indoleExample 16 5-Methoxy-2-methyl-1-[4-(4-pyrrolidin-1-ylbut-1- IC₅₀ < 0.1ynyl)phenyl]-1H-indole Example 17(5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1- K_(i) < 0.01yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1- ylmethanone Example 181-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.01indole-2-carboxylic acid cyclobutylamide Example 191-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.01indole-2-carboxylic acid cyclopentylamide Example 201-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.1indole-2-carboxylic acid cyclohexylamide Example 211-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.1indole-2-carboxylic acid cycloheptylamide Example 22(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}- K_(i) < 0.011H-indol-2-yl)pyrrolidin-1-ylmethanone Example 232-(3-Morpholin-4-ylpropoxy)-6,7,8,9- K_(i) < 0.01tetrahydropyrido[1,2-a]indole Example 24(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}- K_(i) < 0.011H-indol-2-yl)morpholin-4-ylmethanone Example 251-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.01indole-2-carboxylic acid butylamide Example 261-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.01indole-2-carboxylic acid isobutylamide Example 271-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H- K_(i) < 0.01indole-2-carboxylic acid cyclohexylmethylamide Example 285-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1- K_(i) < 0.01yl)propoxy]phenyl}-1H-indole-2-carboxylic acid cyclohexylamide Example29 1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2- K_(i) < 0.01carboxylic acid ethyl ester Example 30{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2- K_(i) < 0.01yl}methanol Example 31 2-Methoxymethyl-1-[4-(3-pyrrolidin-1- K_(i) <0.01 ylpropoxy)phenyl]-1H-indole Example 322-Cyclohexyloxymethyl-1-[4-(3-pyrrolidin-1- K_(i) < 0.01ylpropoxy)phenyl]-1H-indole Example 332-Isopropoxymethyl-1-[4-(3-pyrrolidin-1- K_(i) < 0.01ylpropoxy)phenyl]-1H-indole Example 342-Cyclopentyloxymethyl-1-[4-(3-pyrrolidin-1- K_(i) < 0.01ylpropoxy)phenyl]-1H-indole Example 35{5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H- K_(i) < 0.01indol-2-yl}methanol Example 362-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]- IC₅₀ < 0.11H-indole Example 372-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole K_(i) < 0.01Example 38 2-Cyclopropyl-1-[4-(3-pyrrolidin-1- K_(i) < 0.01ylpropoxy)cyclohexyl]-1H-indole Example 392-(2-Methoxyethyl)-1-[4-(3-pyrrolidin-1- K_(i) < 0.01ylpropoxy)phenyl]-1H-indole Example 402-{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2- K_(i) < 0.01yl}ethanol Example 41 5-Methoxy-2-methoxymethyl-1-[4-(3-pyrrolidin-1-yl-K_(i) < 0.01 propoxy)-phenyl]-1H-indole Example 425-fluoro-2-methoxymethyl-1-[4-(3-pyrrolidin-1-yl- K_(i) < 0.01propoxy)-phenyl]-IH-indole Example 435-methyl-2methoxymethyl-1-[4-(3-pyrrolidin-1-yl- K_(i) < 0.01propoxy)-phenyl]-1H-indole Example 44 ^(a) IC₅₀ values were determinedusing FLIPR.

What is claimed is:
 1. A compound of the formula:

wherein spacer is

Y is CH or N, provided that if Y is CH then n is 0-2; if Y is N then nis 2-4; if Y is CH then R¹ and R² taken together are—(CH₂)_(a)—NR¹¹—(CH₂)₂— where a is 1-2 which when taken together with Yform a piperidine or pyrrolidine ring which is optionally substitutedwith 1-3 groups selected from fluoro, fluoroalkyl, (C₁-C₄)alkyl, alkoxy,aryl, (C₃-C₇)cycloalkyl, heterocycloalkyl containing 1-2 hetero atomsselected from (O, S) and (C₁-C₅)alkyl-O—(C₁-C₅)alkyl; and if Y is N thenR¹ and R² independently are (C₁-C₅)alkyl or (C₃-C₆)cycloalkyl, or R¹ andR² taken together with the nitrogen to which they are attached form a5-7 member heterocyclic ring system with 0-1 additional hetero atomsselected from O and S which is optionally substituted with 1-3(C₁-C₅)alkyl, fluoroalkyl or (C₃-C₆)cycloalkyl groups, or R¹ and R²taken together are —(CH₂)_(a)—NR¹¹—(CH₂)₂—, where a is 2-3, which whentaken together with Y form a piperazine or homopiperazine ring which isoptionally substituted with 1-3 groups selected from fluoro,fluoroalkyl, (C₁-C₄)alkyl, alkoxy, aryl, (C₃-C₇)cycloalkyl,heterocycloalkyl containing 1-2 hetero atoms selected from (O, S) and(C₁-C₅)alkyl-O—(C₁-C₅)alkyl; R³ is 0-2 of groups selected from halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, heterocycloalkyl containing 1-3 heteroatoms selected from (O, S) and (C₁-C₃)alkyl-O—(C₁-C₅)alkyl; R⁴ and R⁵are selected independently from H, (C₁-C₅)alkyl, (C₁-C₈)alkoxy,(C₁-C₅)alkyl-O—(C₁-C₅)alkyl, (C₃-C₆)cycloalkyl, aryl, CF₃ and halogen;R⁶ is CONR⁷R⁸, —(CH₂)_(x)—O—R⁹, alkyl, fluoroalkyl or SO₂NR⁷R⁸; x is1-4; R⁷ and R⁸ independently are hydrogen, (C₁-C₅)alkyl or(C₃-C₆)cycloalkyl, or R⁷ and R⁸ together with the nitrogen to which theyare attached form a 5-7 member heterocyclic ring system with 0-1additional hetero atoms selected from O, S and N(R¹⁰), wherein theresulting ring is optionally substituted with 1-3 (C₁-C₅)alkyl or(C₃-C₆)cycloalkyl groups; R⁹ is hydrogen, (C₁-C₅)alkyl,(C₃-C₇)cycloalkyl or aryl; R¹⁰ is (C₁-C₅)alkyl, (C₁-C₈)alkoxy,(C₁-C₅)alkyl-O—(C₁-C₅)alkyl, (C₃-C₆)cycloalkyl or aryl; and R¹¹ is(C₁-C₅)alkyl, fluoroalkyl or (C₃-C₆)cycloalkyl and the pharmaceuticallyacceptable salts, and individual stereoisomers thereof.
 2. A compound ofclaim 1 selected from the group consisting of:2-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;2-Methyl-1-[4-(3-piperidin-1-ylpropoxy)phenyl]-1H-indole;2-Methyl-1-[4-(3-(2R-methylpyrrolidin-1-yl)propoxy)phenyl]-1H-indole;1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;5-Methoxy-2-methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;5-Methyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;5-Bromo-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;4-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;5-Methoxy-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;5-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;2,5-Dimethyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;6-Chloro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;2-Methyl-5-fluoro-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;1-[3-Methoxy-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole;1-[3-Chloro-4-(3-pyrrolidin-1-ylpropoxy)phenyl]-2-methyl-1H-indole;2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;5-Methoxy-2-methyl-1-[4-(4-pyrrolidin-1-ylbut-1-ynyl)phenyl]-1H-indole;(5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanone;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclobutylamide;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclopentylamide;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylamide;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cycloheptylamide;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)pyrrolidin-1-ylmethanone;2-(3-Morpholin-4-ylpropoxy)-6,7,8,9-tetrahydropyrido[1,2-a]indole;(1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indol-2-yl)morpholin-4-ylmethanone;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid butylamide;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid isobutylamide;1-{4-[3-(2R-Methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylmethylamide;5-Methoxy-1-{4-[3-(2R-methylpyrrolidin-1-yl)propoxy]phenyl}-1H-indole-2-carboxylicacid cyclohexylamide;1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indole-2-carboxylic acid ethylester; 2-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole;2-Propyl-1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1H-indole; and2-Cyclopropyl-1-[4-(3-pyrrolidin-1-ylpropoxy)cyclohexyl]-1H-indole.
 3. Amethod of treating a condition selected from obesity, age-related memorydysfunction, Parkinson's disease, attention deficit disorder,schizophrenia, epilepsy, narcolepsy, sleep apnea, insomnia, disturbedbiological and circadian rhythms, hyper- and hyposomnolence, pain andmigraines in a patient comprising administering an effective amount ofat least one compound of claim 1 to a patient in need of such treatment.